rs919196

chr20-58909030-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000516.7(GNAS):c.531-132T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 796,524 control chromosomes in the GnomAD database, including 15,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3667 hom., cov: 32)
  • Exomes 𝑓: 0.18 (11474 hom.)
• Consequence: GNAS NM_000516.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

Genes affected

GNAS (HGNC:4392): (GNAS complex locus) This locus has a highly complex imprinted expression pattern. It gives rise to maternally, paternally, and biallelically expressed transcripts that are derived from four alternative promoters and 5' exons. Some transcripts contain a differentially methylated region (DMR) at their 5' exons, and this DMR is commonly found in imprinted genes and correlates with transcript expression. An antisense transcript is produced from an overlapping locus on the opposite strand. One of the transcripts produced from this locus, and the antisense transcript, are paternally expressed noncoding RNAs, and may regulate imprinting in this region. In addition, one of the transcripts contains a second overlapping ORF, which encodes a structurally unrelated protein - Alex. Alternative splicing of downstream exons is also observed, which results in different forms of the stimulatory G-protein alpha subunit, a key element of the classical signal transduction pathway linking receptor-ligand interactions with the activation of adenylyl cyclase and a variety of cellular reponses. Multiple transcript variants encoding different isoforms have been found for this gene. Mutations in this gene result in pseudohypoparathyroidism type 1a, pseudohypoparathyroidism type 1b, Albright hereditary osteodystrophy, pseudopseudohypoparathyroidism, McCune-Albright syndrome, progressive osseus heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-58909030-T-C is Benign according to our data. Variant chr20-58909030-T-C is described in ClinVar as [Benign]. Clinvar id is 1277318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNAS	NM_000516.7	c.531-132T>C		intron_variant		ENST00000371085.8
GNAS	NM_016592.5	c.*437-132T>C		intron_variant		ENST00000371075.7
GNAS	NM_080425.4	c.2460-132T>C		intron_variant		ENST00000371100.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNAS	ENST00000371075.7	c.*437-132T>C		intron_variant		1	NM_016592.5
GNAS	ENST00000371085.8	c.531-132T>C		intron_variant		1	NM_000516.7
GNAS	ENST00000371100.9	c.2460-132T>C		intron_variant		5	NM_080425.4

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32259 AN: 152008 Hom.: 3664 Cov.: 32

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.181 AC: 116609 AN: 644398 Hom.: 11474 Cov.: 8 AF XY: 0.177 AC XY: 61788 AN XY: 349712

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.185

Gnomad4 OTH exome AF: 0.196

GnomAD4 genome AF: 0.212 AC: 32290 AN: 152126 Hom.: 3667 Cov.: 32 AF XY: 0.209 AC XY: 15527 AN XY: 74368

Gnomad4 AFR AF: 0.299

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.212

Alfa AF: 0.193 Hom.: 2826

Bravo AF: 0.220

Asia WGS AF: 0.180 AC: 626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.96
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs919196; hg19: chr20-57484085; COSMIC: COSV55672785; COSMIC: COSV55672785;